CN101843669B - Chinese medicinal effective-part composition for treating coronary heart diseases - Google Patents
Chinese medicinal effective-part composition for treating coronary heart diseases Download PDFInfo
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Abstract
The invention discloses a Chinese medicinal composition for preventing or treating coronary heart diseases. The composition can safely and effectively prevent or treat coronary heart diseases. The composition comprises red sage roots extract taking total phenolic acid of red sage roots as effective parts, radix pseudo-ginseng extract taking total saponin of radix pseudo-ginseng as effective parts, long pepper extract taking total alkaloid of long pepper as effective parts, as well as succinum extract taking total diterpene of succinum as effective parts, and utilizes the therapeutical effect of the compatibility of the components on coronary heart diseases to give play to multi-link multi-channel multi-target effect of promoting blood circulation to remove blood stasis, activating collaterals and relieving pain. The composition can be medically acceptable solid oral preparations, such as tablets, capsules (soft capsules or hard capsules), granules and other types of preparations. The composition is used for treating coronary heart diseases, heart failure, arrhythmia and the like, and has the advantages of use safety, effectiveness, stability, controllability and convenience.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of medicine for the treatment of coronary heart disease, specifically the pharmaceutical composition of forming by Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, succinum total sesquiterpene.
Background technology
Coronary heart disease is one of major disease of serious harm people ' s health,, becomes " the first human killer " because of its sickness rate height and mortality rate height.Current research result at Chinese middle-aged population shows, in the period of 1998 to 2008, the Chinese male Incidence of CHD increased by 26.1% the same period more in the past, the women increases by 19%, China dies from the number of various coronary heart disease every year and estimates to surpass 1,000,000, is the fastest disease that rises during China resident cause of the death constitutes.Along with Chinese society aging and human life style's change, China will become an incidence of coronary heart disease big country.Therefore, the drug research of reinforcement treatment coronary heart disease has important society and economic implications.
Along with the limitation of Western medicine is familiar with by people and the change of world's spectrum of disease and medical model gradually, advocating natural drug is just becoming a kind of worldwide trend, and the Chinese medicine industry is faced with unprecedented opportunities.But, the low inferior reason of level of modernization owing to the Chinese medicine industry, problems such as Chinese medicine industry ubiquity production technology backwardness, unstable product quality, scientific and technological content are low cause a little less than the competitiveness in the international market of Chinese medicine industry, and the Chinese medicine industry is faced with stern challenge.Compound preparation is the characteristic of Chinese medicine clinical practice, also is the principal mode of Chinese medicine preparation.It is clear and definite substantially that the effective ingredient in Chinese compositions has effective substance, the mechanism of action is clear relatively, clinical adaptation disease is more definite, and have than strong specific aim, safe and effective, adapting to the Technology of modern manufacturing industry and the advantage of quality standard, is the novel modern Chinese medicine that possesses " triple effect " (efficient, quick-acting, long-acting), " three is little " (dosage, toxicity, side effect are little), " three just " (store, carry, taking convenience) characteristics.
Coronary heart disease belongs to categories such as Chinese medicine precordial pain with cold limbs, the thoracic obstruction, angina pectoris, and its pathogenesis can be summarized as " stagnation of QI and blood may bring about pain " and " not Rong Ze pain ".Modern a large amount of clinical research shows that coronary heart disease is the advantage disease of Chinese medicine, compares with Western medicine, and Chinese medicine coronary heart disease has following advantage: toxic and side effects is less relatively, is suitable for prolonged application; A medicine can act on a plurality of pathology links of coronary heart disease; Improve symptom that the patient follows as breathe hard, weak, spirit depressing etc. is comparatively obvious; Can improve patient's life quality, reduce patient economy burden, meet the requirement of health economics.Basic research confirms that methods such as blood circulation promoting and blood stasis dispelling, benefiting QI for activating blood circulation, heat-clearing and toxic substances removing have multiple actions such as blood fat reducing, coronary artery dilating, anticoagulant, effect has comprised aspects such as influencing endothelial function, vulnerable plaque, platelet activation, left ventricular remodeling, vascular remodeling, angiogenesis, embodied Chinese medicine and started with, at the comprehensive Pathophysiology of adjusting coronary heart disease, improve aspect such as clinical symptoms the irreplaceable advantage of chemical synthetic drug is arranged from integrally-regulated.Cure the disease means and method of Chinese medicine comes from nature in addition, and few side effects is advocated under the green background in the world, the domestic and even international focus of Chinese patent medicine development having become of treatment coronary heart disease.In the Chinese patent medicine of present numerous treatment coronary heart disease, be that the Chinese patent medicines such as Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Radix Puerariae flavone of main active more and more are subjected to people and pay attention to effective site, the effect of the various effective ingredient in Chinese of treatment coronary heart disease is respectively given priority to different, has the great demand of drug combination clinically.Therefore, provide effective substance clear and definite substantially, the mechanism of action is clear relatively, and clinical adaptation disease specific aim is stronger, safe and effective, adapts to the Technology of modern manufacturing industry and the effective ingredient in Chinese compound preparation of quality standard and has the important clinical meaning.
Summary of the invention
The purpose of this invention is to provide a kind of effective ingredient in Chinese compositions that is used for the treatment of coronary heart disease, its effective substance is clear and definite substantially, the mechanism of action is clear relatively, quality controllable, and energy blood circulation promoting and blood stasis dispelling, removing obstruction in the collateral to relieve pain, produce synergism, raising evident in efficacy provides a kind of better efficacy clinically, safer, effective ingredient in Chinese compound and preparation thereof more easily.
The present invention is implemented by following technical proposals.
The raw materials used weight proportion of pharmaceutical composition provided by the invention is: Radix Salviae Miltiorrhizae total phenolic acids 1.25-1.5 part, Radix Notoginseng total arasaponins 1-1.5 part, 0.02 ~ 0.13 part of Fructus Piperis Longi total alkaloids, 0.02 ~ 0.09 part of succinum total sesquiterpene.
Pharmaceutical dosage form of the present invention is oral formulations such as tablet, drop pill, capsule, soft capsule, granule, and adjuvant is the corresponding adjuvant of acceptable on the pharmaceutics.
The used Radix Salviae Miltiorrhizae total phenolic acids content of the present invention is not less than 50%, and content of the total saponins in radix notoginseng is not less than 50%, and the Fructus Piperis Longi total alkaloid content is not less than 50%, and succinum total sesquiterpene content is not less than 50%.
The present invention treats in the pharmaceutical composition of coronary heart disease, and described Radix Salviae Miltiorrhizae total phenolic acids extracts from Radix Salviae Miltiorrhizae, and Radix Notoginseng total arasaponins extracts from Radix Notoginseng, and the Fructus Piperis Longi total alkaloids extracts from Fructus Piperis Longi, and the succinum total sesquiterpene extracts from succinum; The content of described Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, succinum total sesquiterpene all meets above-mentioned requirements.
The all available literature method preparation of active component in the said composition [1-4] also can be bought from market, can also oneself prepare.
Described Radix Salviae Miltiorrhizae total phenolic acids can be with the preparation of following method: red rooted salvia is ground into coarse powder, with ethanol ultrasonic extraction 2 times, adds 10 times of amount soak with ethanol supersound extraction after 12 hours for the first time; For the second time add 5 times of ethanol ultrasonic extraction, each 1 hour.Merge extractive liquid,, filter, filtrate is concentrated into 0.2～0.8g raw medicinal herbs/ml, adds the SIPI905 macroporous adsorbent resin, washes with water earlier except that impurity such as saccharide react to molish to be negative, use 3～4 times of volume 70% ethanol elutions then, collect eluent, concentrating under reduced pressure, vacuum drying is to constant weight, promptly get Radix Salviae Miltiorrhizae total phenolic acids content and must not be lower than 50%, wherein content of danshinolic acid B must not be lower than 30%.
During above-mentioned supersound extraction, power 250w, frequency 30KHz.
The assay of salvianolic acid B (high performance liquid chromatography) chromatographic condition and system suitability test: B in the above-mentioned Radix Salviae Miltiorrhizae total phenolic acids: with octadecylsilane chemically bonded silica is filler; Mobile phase is methanol: acetonitrile: formic acid: water (30: 10; 1; 59); Flow velocity is 1mL/min; Column temperature is 25 ℃; The detection wavelength is 286nm, and number of theoretical plate is pressed the salvianolic acid B peak and calculated more than 2000.
The preparation of reference substance solution: it is an amount of that precision takes by weighing the salvianolic acid B reference substance, adds 75% methanol and make the solution that every 1mL contains 0.44mg, promptly.
The preparation of need testing solution: get 2 of this product, porphyrize is got the about 0.2g of powder, and accurate the title decides, and puts in the tool plug conical flask, the accurate 75% methanol 50mL that adds claims to decide weight, and reflux 1h takes out, and claims to decide weight after the cooling again, supply the weight that subtracts mistake with 75% methanol, shake up, filter, promptly.
Algoscopy: accurate respectively reference substance and each 10 μ l of need testing solution of drawing, inject chromatograph of liquid and measure.
The assay of above-mentioned Radix Salviae Miltiorrhizae total phenolic acids (ultraviolet-visible light photometry)
The preparation of reference substance solution: precision takes by weighing salvianolic acid B 25mg and places the 100mL measuring bottle, adds methanol and makes dissolving in right amount and be diluted to scale, shakes up, and precision is measured above-mentioned solution 10mL, and thin up is configured to the reference substance solution of 25 μ g/mL to 100mL.
The preparation of need testing solution: get the about 0.1g of this product, the accurate title, decide, and puts in the 50mL measuring bottle, add water and make dissolving in right amount and be diluted to scale, shake up, precision is measured 10mL, put in the separatory funnel, add the saturated 0.1mol/mL hydrochloric acid 50mL of ethyl acetate, shake up, use the saturated ethyl acetate extraction of 0.1mol/mL hydrochloric acid 3 times, each 20mL, get acetic acid ethyl fluid, water bath method, residue add dissolve with methanol and quantitatively are transferred in the 25mL measuring bottle, add methanol and be diluted to scale, shake up, precision is measured above-mentioned solution 10mL and is put in the 100mL measuring bottle, and thin up is to scale, shake up, filter, get subsequent filtrate, promptly.
Algoscopy: getting reference substance and need testing solution respectively, is blank with the solvent, according to ultraviolet visible spectrophotometry (appendix VA of Chinese Pharmacopoeia version in 2005), measures trap at 286nm wavelength place, calculates promptly.
The commercial goods that Radix Notoginseng total arasaponins in the present composition can directly be bought, the product of purchase must meet national standard.Preferred Radix Notoginseng total arasaponins prepares according to following method: pseudo-ginseng is adopted 70% ethanol extraction, filter, filtrate decompression concentrates, cross macroporous adsorptive resins, use 80% ethanol elution, eluent decolouring back concentrating under reduced pressure, refining, drying promptly gets Radix Notoginseng total arasaponins, contains wherein that arasaponin R1 must not be less than 5.0%, the ginsenoside Rg1 must not be less than 20.0%, the ginsenoside Rb1 must not be less than 25.0%.
Fructus Piperis Longi total alkaloids in the present composition can prepare with following method: adopt SFE-CO
2The extraction, promptly get the Fructus Piperis Longi total alkaloids and must not be lower than 50%, wherein content of piperine must not be lower than 30%, the employing cyclodextrin inclusion compound, the result with 2～6 times to supercritical CO
2The β-CDBao He of extract adds 4 times of water gagings, and enclose time 2h promptly gets beta-CD inclusion.
The assay (high performance liquid chromatography) of piperine in the above-mentioned Fructus Piperis Longi total alkaloids
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; Methanol: aqueous solution (77: 23) is a mobile phase; Flow velocity is 1mL/min; Column temperature is 25 ℃; The detection wavelength is 343nm.Press the piperine peak and calculate, number of theoretical plate is more than 2000.
The preparation of reference substance solution: it is an amount of that precision takes by weighing the piperine reference substance, adds methanol and make the solution that every 1mL contains 40 μ g, promptly.
The preparation of need testing solution: get 2 of this product, porphyrize is got the about 0.5g of powder, accurate claims surely, puts in the 50mL measuring bottle, adds methanol 45mL, and supersound process (power 250W, frequency 20kHz) 30min is put coldly, adds methanol to scale, shakes up, and filters, and gets subsequent filtrate, promptly.
Algoscopy: accurate respectively reference substance and each 10 μ l of need testing solution of drawing, inject chromatograph of liquid and measure.
The mensuration of above-mentioned Fructus Piperis Longi total alkaloids
The preparation of reference substance solution: precision takes by weighing piperine reference substance 5mg, puts in the 10mL measuring bottle, adds dissolve with methanol and is diluted to scale, shake up, get in 2mL to the 25mL volumetric flask, add 5mL buffer (pH=5) respectively, 2mL bromothymol blue test solution shakes up, and adds the chloroform standardize solution again, fully shake up, move in the separatory funnel, place layering, get chloroform layer (subnatant), filter, promptly.
The preparation of need testing solution: get the about 0.5g of this product powder, the accurate title, decide, and puts in the 50mL measuring bottle, add chloroform 35mL, supersound process (power 250W, frequency 20kHz) 30min, after the cooling, add buffer, the 2mL bromothymol blue test solution of 5mL pH=5, shake up, add the chloroform standardize solution again, fully shake up, move in people's separatory funnel, place layering, get chloroform layer (subnatant) and filter, promptly.
Algoscopy: getting reference substance and need testing solution respectively, is blank with the chloroform, according to ultraviolet visible spectrophotometry (appendix VA of Chinese Pharmacopoeia version in 2005), measures trap at 343nm wavelength place, calculates promptly.
Succinum total sesquiterpene in the present composition can prepare with following method: the succinum total sesquiterpene in the present composition can prepare with following method: adopt SFE-CO
2The extraction, promptly get total sesquiterpene content and must not be lower than 50%, the employing cyclodextrin inclusion compound, the result with 2～6 times to supercritical CO
2The β-CDBao He of extract adds 4 times of water gagings, and enclose time 2h promptly gets beta-CD inclusion.
Another object of the present invention has provided preparation of drug combination method of the present invention, and this method can adopt the conventional method of pharmaceutical field, uses conventional pharmaceutic adjuvant to carry out.After for example adopting conventional method with Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, succinum total sesquiterpene uniform mixing, mix, make various peroral dosage forms then with carrier or adjuvant commonly used on any one or more than one pharmaceutics.Described carrier is excipient, filler, diluent, lubricant, wetting agent, disintegrating agent, surfactant, antiseptic, sweeting agent, aromatic etc. for example.Particularly, for example starch, dextrin, lactose, microcrystalline Cellulose, hydroxypropyl methylcellulose, Polyethylene Glycol, magnesium stearate, micropowder silica gel, glucose, mannitol, xylitol, glycine etc. of described carrier.
As required, pharmaceutical composition of the present invention can be made into the preparation that is suitable for oral medication, can be following arbitrary dosage form: tablet, capsule, soft capsule, granule, drop pill, dispersible tablet, oral cavity disintegration tablet, pill.
Another object of the present invention has provided pharmaceutical composition of the present invention in the application for the treatment of aspects such as coronary heart disease and heart failure, arrhythmia.
Compared with prior art, the invention has the beneficial effects as follows: this pharmaceutical composition contains Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, succinum total sesquiterpene, and energy blood circulation promoting and blood stasis dispelling, generation synergism prove that through pharmacodynamics test it is evident in efficacy.
The specific embodiment
For the present invention is further described in detail, provide specific embodiment, but only the present invention is illustrated in conduct, rather than in order to limit the scope of the invention.
Granule, tablet or the capsule formulation of embodiment 1 pharmaceutical composition of the present invention
The preparation of granule: adopt conventional preparation granule technology, get 1.5 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1.5 parts of Radix Notoginseng total arasaponinss, 0.02 part of Fructus Piperis Longi total alkaloids, 0.02 part of succinum total sesquiterpene, right amount of auxiliary materials.Mixing is granulated, and sieves, and drying makes the granule forms of pharmaceutical compositions.
The preparation of tablet: through further tabletting, drying promptly makes and contains 1.5 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1.5 parts of Radix Notoginseng total arasaponinss, 0.02 part of Fructus Piperis Longi total alkaloids, the pharmaceutical composition of the Tabules that the succinum total sesquiterpene is 0.02 part with the granule that makes.
The preparation of capsule: the granule that makes is incapsulated shell, make capsule, promptly make and contain 1.2 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1 part of Radix Notoginseng total arasaponins, 0.02 part of Fructus Piperis Longi total alkaloids, the pharmaceutical composition of the Tabules that the succinum total sesquiterpene is 0.02 part.
The drops of embodiment 2 present compositions
Preparation: adopt the technology of conventional preparation drop pill, get 1.25 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1.2 parts of Radix Notoginseng total arasaponinss, 0.10 part of Fructus Piperis Longi total alkaloids, 0.08 part of succinum total sesquiterpene, right amount of auxiliary materials makes the drop pill of this pharmaceutical composition.
The soft capsule dosage form of embodiment 3 present compositions
Preparation: adopt the technology of conventional preparation soft capsule, get 1.25 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1 part of Radix Notoginseng total arasaponins, 0.12 part of Fructus Piperis Longi total alkaloids, 0.07 part of succinum total sesquiterpene, right amount of auxiliary materials, mixing, make capsule casing material with gelatin, be pressed into soft capsule, make the soft capsule of this pharmaceutical composition.
The micropill dosage form of embodiment 4 present compositions
Preparation: adopt the technology of conventional preparation micropill, get 1.25 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1 part of Radix Notoginseng total arasaponins, 0.05 part of Fructus Piperis Longi total alkaloids, 0.05 part of succinum total sesquiterpene, right amount of auxiliary materials makes the micropill of this pharmaceutical composition.
The oral cavity disintegration tablet of embodiment 5 present compositions
Preparation: adopt the technology of conventional preparation oral cavity disintegration tablet, get 1.25 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1 part of Radix Notoginseng total arasaponins, 0.07 part of Fructus Piperis Longi total alkaloids, 0.04 part of succinum total sesquiterpene, right amount of auxiliary materials makes the oral cavity disintegration tablet of this pharmaceutical composition.
The dispersible tablet of embodiment 6 present compositions
Preparation: adopt the technology of conventional preparation dispersible tablet, get 1.25 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1 part of Radix Notoginseng total arasaponins, 0.03 part of Fructus Piperis Longi total alkaloids, 0.03 part of succinum total sesquiterpene, right amount of auxiliary materials makes the dispersible tablet of this pharmaceutical composition.
The test of pesticide effectiveness of embodiment 7 present compositions
(1) the prescription compatibility of medicines optimization test of the present composition
Drug effect for the Radix Salviae Miltiorrhizae total phenolic acids of investigating different compatibilities, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, succinum total sesquiterpene, find the prescription of optimum medicine efficacy, this test is selected Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, succinum total sesquiterpene as 4 factors investigating, not have and promising 2 levels, carry out the L of four factors, two levels
8(2
7) test.
Table 1 factor level design table
Table 2L
8(2
7) orthogonal array
Animal is divided into 9 groups at random: model group, diltiazem group, Fructus Piperis Longi total alkaloids+succinum total sesquiterpene group, Radix Notoginseng total arasaponins+succinum total sesquiterpene group, Radix Notoginseng total arasaponins+Fructus Piperis Longi total alkaloids group, Radix Salviae Miltiorrhizae total phenolic acids+succinum total sesquiterpene group, Radix Salviae Miltiorrhizae total phenolic acids+Fructus Piperis Longi total alkaloids group, Radix Salviae Miltiorrhizae total phenolic acids+Radix Notoginseng total arasaponins group, Radix Salviae Miltiorrhizae total phenolic acids+Radix Notoginseng total arasaponins+Fructus Piperis Longi total alkaloids+succinum total sesquiterpene group.Medicine is molten to desired concn with 0.5%CMC, and the administration volume is 3ml/kg, and route of administration is a duodenum.
Test is carried out according to literature method.After the ligation 2 hours, 5 of the following crosscuts of heart ligature, multi-media color pathology picture and text analytical system is adopted in N-BT dyeing, measures total myocardial area and infarcted myocardium area, observation myocardial infarction degree with fixing image distance; The result carries out statistical procedures (t check).
The different compatibilities of table 3 present composition (Hu Xinkang) to the influence of myocardial infarction rat infarct size (X ± SD, n=8)
Annotate: compare * P＜0.05, * * P＜0.01 with model group.
Directly perceived and the variance analysis by quadrature, the result shows that Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, succinum total sesquiterpene all act on significantly (P＜0.05) to the influence of myocardial infarction area, therefore selects for use Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, 4 kinds of extract compatibilities of succinum total sesquiterpene to protect heart health prescription.
(2) influence of different proportioning compositions muscle infarction models test
The function of resisting myocardial ischemia of the present composition is proved by following pharmacodynamics test: select 30 of healthy adult dogs for use, the male and female dual-purpose, be divided into 5 groups at random, every group 6: with 1.25 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1 part of Radix Notoginseng total arasaponins, 0.02 part of Fructus Piperis Longi total alkaloids, the succinum total sesquiterpene is compositions A group for 0.02 part, with 1.25 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1.2 parts of Radix Notoginseng total arasaponinss, 0.04 part of Fructus Piperis Longi total alkaloids, the succinum total sesquiterpene is compositions B group for 0.06 part, 1.5 parts of Radix Salviae Miltiorrhizae total phenolic acidss, 1.5 parts of Radix Notoginseng total arasaponinss, 0.06 part of Fructus Piperis Longi total alkaloids, succinum total sesquiterpene 0.08 is compositions C group, negative control normal saline group, Western medicine positive drug diltiazem group, totally 5 groups.
Test method: respectively at before the ischemia, behind the ischemia 15min (before the medicine), medicine 15,30,60,90,120, the variation of 180min record visceral pericardium point diagram.Visceral pericardium point diagram observation index: the summation with lead number (NST) and ST section lift-off value more than the ST section rising 2mv is the variation of index observing administration front and back, and the degree of calculating myocardium ischemia and scope.Get arteriovenous blood, measure coronary sinus vein, arterial oxygen content respectively with blood oxygen analyzer, and by coronary flow (CABF) calculating myocardium oxygen consumption (MOC), serum creatine kinase (CK), lactic acid dehydrogenase (LDH), endothelin level (ET), thromboxane (TXB2) and 6-ketone-prostaglandin F
1 α(6-Keto-PGF
1 α).The 180min record finishes behind the medicine, takes off heart immediately, and the flushing of NS liquid is weighed, and under the heart ligature, is parallel to coronary sulcus and equably ventricle partly is cut into 5, places nitro tetrazole orchid (N-BT) dye liquor, room temperature dyeing 15min.The infarct (the non-dyeing of N-BT district) that the medical images analytical system is measured every myocardium bilateral and non-infarct (N-BT dye district) calculate area, the ventricle gross area and the infarct gross area of every cardiac muscle.Calculating infarct accounts for ventricle and accounts for dirty whole-heartedly percentage ratio.Experimental result is carried out statistical procedures, judges its significance with the t check.
Experimental result:
1, to the dog degree of myocardial ischemia (influence of ∑-ST):
The results are shown in Table 4.Through duodenal administration, present composition A, B, C group all has and obviously alleviates the degree of myocardial ischemia (effect of ∑-ST).Wherein the 30min medicine can play a role behind the compositions C group medicine, and continue to 180min behind the medicine, animal ∑-ST by medicine before (387.81 ± 37.67) mv reduce to (205.38 ± 15.17) mv, (46.62 ± 11.72) % that descended, compositions C group before ∑-ST of 30min～180mi n and medicine and and the matched group comparing difference have statistical significance (P＜0.01～0.05); The 45min medicine can play a role behind the compositions B group medicine, and continue to 180min behind the medicine, animal ∑-ST by medicine before (394.24 ± 62.59) mv reduce to (241.70 ± 71.37) mv, (30.16 ± 16.69) % that descended, compositions B group has statistical significance (P＜0.01～0.05) at ∑-ST and the matched group comparing difference of 45min～180min; The 60min medicine can play a role behind the compositions A group medicine, and continue to 120min behind the medicine, animal ∑-ST by medicine before (399.22 ± 60.53) mv reduce to (297.56 ± 59.98) mv, (25.57 ± 13.09) % that descended, compositions A group has statistical significance (P＜0.05) at ∑-ST and the matched group comparing difference of 60min～120min.
2, to the influence of dog myocardial ischemia scope (N-ST)
The results are shown in Table 5.After matched group fed 0.5%CMC, myocardial ischemia scope (N-ST) did not have obviously change.Compositions A, B, C group all has the effect that reduces myocardial ischemia scope (N-ST) in various degree, and wherein the 30min medicine can play a role behind the compositions C group medicine, and continues to 180min behind the medicine.Animal N-ST by medicine before (29.93 ± 0.82) individual mapping point reduce to (23.83 ± 3.31) individual mapping point, before (18.80 ± 10.55) % that descended, the N-ST of compositions C group 30min～180min and medicine and and the matched group comparing difference have statistical significance (P＜0.01～0.05); The 45min medicine can play a role behind the compositions B group medicine, and continue to 180min behind the medicine, animal N-ST by medicine before 29.55 ± 0.75mv mapping point reduce to (24.87 ± 3.27) individual mapping point, reach the matched group comparing difference before (15.39 ± 12.17) % that descended, compositions B group 45min～180min and medicine and have statistical significance (P＜0.01～0.05); The 60min medicine plays a role behind the compositions A group medicine, and continue to 90min behind the medicine, animal N-ST by medicine before (29.37 ± 0.86) mv mapping point reduce to (28.11 ± 1.01) individual mapping point, reach the matched group comparing difference before (4.92 ± 2.78) % that descended, compositions B group 45min～180min and medicine and have statistical significance (P＜0.05).
Above result shows that compositions A, B, C all have significant improvement effect to experimental acute dog myocardial ischemia, can significantly alleviate degree of myocardial ischemia and (∑-ST), dwindle myocardial ischemia scope (N-ST).
3, to the influence of dog acute myocardial infarction scope (N-BT staining mensuration):
The results are shown in Table 6.Protect heart health compositions A, B, C can reduce animal cardiac muscle infarct area, with matched group significant difference (P＜0.05 or P＜0.01) is arranged more all, wherein compositions C group myocardial infarction area area accounts for (2.91 ± 1.30) %, (6.54 ± 2.41) % of heart and ventricle respectively, has statistical significance (P＜0.01) with the matched group comparing difference; Compositions B group myocardial infarction area area account for respectively heart and ventricle 4.22 ± 2.45%, (9.17 ± 3.85) %, fall comparing difference with matched group and have statistical significance (P＜0.01); Compositions A group myocardial infarction area area accounts for (5.89 ± 1.71) %, (13.47 ± 5.27) % of heart and ventricle respectively, falls comparing difference with matched group and has statistical significance (P＜0.05).
To sum up, compositions A, B, C promptly write out a prescription Radix Salviae Miltiorrhizae total phenolic acids 1.25-1.5 part, Radix Notoginseng total arasaponins 1-1.5 part, and proportioning between 0.02 ~ 0.13 part of the Fructus Piperis Longi total alkaloids, 0.02 ~ 0.09 part of succinum total sesquiterpene all has good function of resisting myocardial ischemia.
(3) present composition is to the influence of rats in vitro thrombosis and blood viscosity
The effect that the present composition suppresses thrombosis, reduction blood viscosity is proved by following pharmacodynamics test: select 60 of healthy male SD rats for use, divide 6 groups at random, every group 10: the high, medium and low dosage group of Hu Xinkang, protect the high, medium and low dosage group of heart health, the normal control group, model control group, Western medicine positive drug aspirin matched group.Gastric infusion, successive administration 7 days, administration 6d removes the blank group, and it is heavy that each organizes rat skin lower injection adrenalin hydrochloride 0.08mL/100g Mus, and 2 times/day, interval 4h, 2d continuously.Between the injection epinephrine each group rat is immersed 4min in the ice-water bath, 5 ℃ of water temperatures.2d repeats 1 time with the method operation.1h after the last administration, chloral hydrate (300mg/kg) anesthesia, siliconized polyethylene intubate puncture common carotid artery is got 2mL blood and is used for external thrombus mensuration, gets blood 3ml (anticoagulant heparin) and is used for blood viscosity mensuration.
Result of the test is as follows:
1. to the thrombotic influence of blood stasis type rats in vitro
By table 7 as seen, compare with the blank group, model group thrombosis length, weight in wet base, dry weight all significantly increase, and the prompting blood stasis model is duplicated successfully.Compare with model group, thrombosis length, weight in wet base and the dry weight and the matched group that protect each dosage group of heart health sheet, aspirin group more all have significant difference.
Table 7. present composition (Hu Xinkang) to the thrombotic influence of rats in vitro (
)
Annotate: compare with model group
*P＜0.05,
*P＜0.01 (down together)
2. to the influence of blood viscosity
By table 8 as seen, compare with model control group, the whole blood viscosity of protecting heart health extract 360g crude drug/kg dosage group rat is at shear rate 5S
-1, 30S
-11All obviously significantly reduce down (P＜0.01), at shear rate 100S
-, 200S
-1Under obvious reduction (P＜0.05) is arranged; The whole blood viscosity of protecting heart health extract 180g crude drug/kg dosage group rat is at shear rate 5S
-1And 30S
-1All obviously reduce down (P＜0.05), at shear rate 100S
-1, 200S
-1Under reduction trend is arranged, the whole blood viscosity of protecting heart health extract 90g crude drug/kg dosage group rat has downward trend.The whole blood viscosity of aspirin group rat is at shear rate 5S
-1All significantly reduce (P＜0.01), at shear rate 30S
-11All obviously reduce down (P＜0.05), at shear rate 100S
-1, 200S
-1Under reduction trend is arranged.Plasma viscosity of each administration group rat and matched group be no significant difference relatively all.
Table 8. present composition (Hu Xinkang) to the influence of rat blood viscosity (n=10,
)
Annotate: compare with model group
*P＜0.05,
*P＜0.01 (down together)
Experimental result shows, the continuous gastric infusion of rat 7 days protects heart health extract and obviously shortens thrombosis length (P＜0.05), obviously alleviates wet weight of thrombus and dry weight (P＜0.05); Obviously reduce shear rate 5S
-1, 30S
-1And 100S
-1Under whole blood viscosity (P＜0.05).Show the effect that heart health extract has obvious inhibition thrombosis, blood viscosity lowering of protecting.
(4) protect of the influence of heart health to the rabbit platelet aggregation
The effect of present composition anticoagulant, proved by following pharmacodynamics test: select 60 of male Japan large ear rabbits for use, puncture ear medium-sized artery is got the hematometry platelet aggregation rate before the administration, according to platelet aggregation rate level and body weight, divide 6 groups at random, grouping and dosage table 1.1 time/day, continuous irrigation stomach 7d, 1h after the last administration, puncture ear medium-sized artery is got blood, measures platelet aggregation rate.Result of the test is as follows:
Table 9. protect heart health sheet to the influence of rabbit platelet aggregation rate (
N=10, %)
Annotate: compare with the blank group
*P＜0.05,
*P＜0.01.
Table 9 shows that each derivant is induced when assembling, platelet aggregation rate no significant difference between each group before the administration; The platelet aggregation rate and the matched group that protect the heavy dose of group of heart health sheet after the administration relatively are remarkable downward trend (P＜0.01), the platelet aggregation rate of small dose group and matched group be no significant difference relatively, positive group is organized relatively with blank, and platelet aggregation rate has downward trend (P＜0.05).The result shows, protects the effect that heart health extract has remarkable anticoagulant.
The mechanism of action of embodiment 14 present compositions is inquired into
(1) the reoxygenation injury Study on Mechanism of anti-myocardial anoxia/again
In order to investigate the protective effect of the present composition to myocardial cell; this test is duplicated the reoxygenation injury model of anoxia/again with myocardial cell; adopt myocardial cell SOD activity, MDA content and apoptosis myocardial cell correlation factor Bcl-2, Bax to be expressed as the investigation index; cardiac muscle cells is divided into 6 groups (specifically seeing the following form) at random; protect the research of heart health anti-myocardial oxygen free radical injury and apoptosis effect, the result is as follows:
1, the present composition is to anoxia/the active influence of reoxygenation induced injured myocardium cell SOD sees Table 10 again.
The table 10. pair anoxia/active influence of reoxygenation induced injured myocardium cell SOD again (
N=8)
| Group | SOD(u/ml) |
| The blank group | 89.6±11.5 |
| The reoxygenation group of anoxia/again | 34.5±15.4* |
| Diltiazem hydrochloride injection group | 86.2±13.2** |
| Protect heart health low dose group | 62.1±12.6** △ |
| Protect dosage group in the heart health | 79.3±12.8** △△ |
| Protect heart health high dose group | 82.8±10.4** △△ |
Annotate: compare with the blank group: * P＜0.01; With anoxia/the reoxygenation group compares again: * * P＜0.01; Compare with the diltiazem hydrochloride group:
△P＜0.01,
△ △P＞0.05.
The reoxygenation group SOD activity of anoxia/again is than blank group obviously descend (P＜0.01); Each treatment group SOD activity is all than the reoxygenation group of anoxia/significantly raise (P＜0.01).Diltiazem hydrochloride group and present composition group relatively, with low dose group obvious difference (P＜0.01), and with middle and high dosage group difference very not remarkable (P＞0.05).
2, the present composition is to anoxia/influence of reoxygenation induced injured myocardium cell MDA content sees Table 11 again.
The table 11. pair anoxia/influence of reoxygenation induced injured myocardium cell MDA content again (
N=8)
| Group | MDA(nmol/ml) |
| The blank group | 0.94±0.18 |
| The reoxygenation group of anoxia/again | 1.80±0.12* |
| Diltiazem hydrochloride injection group | 1.18±0.13** |
| Protect heart health low dose group | 1.32±0.15** △ |
| Protect dosage group in the heart health | 1.24±0.12** △△ |
| Protect heart health high dose group | 1.26±0.18** △△ |
Annotate: compare with the blank group: * P＜0.01; With anoxia/the reoxygenation group compares again: * * P＜0.01; Compare with the diltiazem hydrochloride group:
△P＜0.05,
△ △P＞0.05.
The reoxygenation group MDA content of anoxia/again is than blank group obviously raise (P＜0.01); The reoxygenation group of each treatment group MDA content and anoxia/more all obviously descend (P＜0.01) of comparing.Diltiazem hydrochloride group and present composition group relatively, with low dose group obvious difference (P＜0.05), and with middle and high dosage group difference very not remarkable (P＞0.05).
3, the present composition is to anoxia/influence of reoxygenation induced injured myocardium apoptosis gene Bcl-2, Bax protein expression sees Table 12 again.
The table 12. pair anoxia/influence of reoxygenation induced injured myocardium apoptosis gene Bcl-2, Bax protein expression again (
N=8)
| Group | Bcl-2 positive cell (%) | Bax positive cell (%) |
| The blank group | 3.85±0.13 | 1.81±0.12 |
| The reoxygenation group of anoxia/again | 2.02±0.15* | 2.89±0.16* |
| Diltiazem hydrochloride injection group | 3.20±0.16** | 1.63±0.13** |
| Protect heart health low dose group | 2.87±0.15** △ | 2.45±0.148** △ |
| Protect dosage group in the heart health | 3.12±0.18** △△ | 1.68±0.14** △△ |
| Protect heart health high dose group | 3.24±0.17** △△ | 1.65±0.12** △△ |
Annotate: compare with the blank group: * P＜0.01; With anoxia/the reoxygenation group compares again: * * P＜0.01; Compare with the diltiazem hydrochloride group:
△P＜0.01,
△ △P＞0.05.
The result shows that anoxia/the reoxygenation group is compared with the blank group again, the expression decreased of bcl-2 (P＜0.01), and bax expresses increases (P＜0.01).High, medium and low dosage group of the diltiazem hydrochloride group and the present composition and anoxia/the reoxygenation group more all can obviously improve the expression (P＜0.01) of bcl-2 again, reduces the expression (P＜0.01) of bax.Diltiazem hydrochloride group and present composition group relatively, with low dose group obvious difference (P＜0.01), and with middle and high dosage group difference very not remarkable (P＞0.05).
(2) to the influence of rats with myocardial ischemia inflammatory factor
In order to investigate the present composition rats with myocardial ischemia inflammatory factor is influenced, adopt coronary artery ligation to duplicate the treating myocardial ischemia damage model, random packet, administration is respectively put to death animal in postoperative 12,24h, adopts ELISA, SABC and PCR method to detect TNF-α respectively, IL-1, VCAM-1, iNOS, the content of NFkB and IkB and expression.The results are shown in down:
1, the present composition is to the influence of rats with myocardial ischemia TNF-α, VCAM-1 expression
Table 13 present composition (Hu Xinkang) to the influence of rats with myocardial ischemia TNF-alpha expression (n=5,
Individual/mm
2)
Annotate: compare * * P＜0.01 with model group; With diltiazem
Group compares, Δ Δ P＜0.01.
The influence that table 14 present composition (Hu Xinkang) is expressed rats with myocardial ischemia VCAM (n=5,
Individual/mm
2)
Annotate: compare * * P＜0.05 with model group; Compare Δ P＜0.05 with the diltiazem group.
From table 13,14 as can be known, TNF-α and VCAM-1 have a certain amount of expression at normal heart, and both express obvious enhancing behind the treating myocardial ischemia damage, diltiazem and protect heart Kang Jun and can reduce its expression, with model group relatively, difference has significance P＜0.05 or P＜0.01; Protect heart health sheet group and diltiazem TNF-α comparing difference has significance, P＜0.05, but do not have significance P＞0.05 in VCAM-1 difference.
2, the present composition is to the influence of rats with myocardial ischemia IL-1 β level, iNos content
IL-1 has the expression of certain level at normal rat serum, IL-1 content increases sharply behind the myocardial ischemia, IL-1 content descends to some extent after protecting heart health and diltiazem, with the model group comparing difference significance (P＜0.05) is arranged, and two group differences also have significance (P＜0.05).See Table 15.
Table 15 present composition (Hu Xinkang) to the influence of myocardial ischemia blood IL-1 β content (n=5,
Individual/mm
2)
Annotate: compare * * P＜0.01 with model group; Compare Δ P＜0.05 with the diltiazem group.
As known from Table 15, iNos content is (5.31 ± 1.13) μ/ml in the normal rat blood, increase sharply behind the myocardial ischemia, than 12h obvious decline is arranged behind the 24h, the ground that nitre Zhuo and the present composition all can be reduced the level of iNos, two groups have significance with model group difference, and two group differences also have significance, P＜0.05.See Table 16.
Table 16 present composition (Hu Xinkang) to the influence of rats with myocardial ischemia blood iNos content (n=5,
Individual/mm
2)
Annotate: compare * P＜0.05 with model group; Compare Δ P＜0.05 with the diltiazem group.
As known from Table 16, IL-1, iNOS have the expression of certain level at normal rat serum, both content increase sharply behind the myocardial ischemia, protect heart health extract and diltiazem the downward modulation IL-1, iNos, two groups with model group difference significance is arranged, and two group differences also have significance, P＜0.05.
3, the present composition is to NFkBP
65, the influence expressed of IKB
NFkBP under the normal condition
65The expression of reduced levels is arranged, NFkBP behind the treating myocardial ischemia damage
65Increase, diltiazem, the present composition all can be reduced NFkBP
65Expression, but diltiazem is not as the present composition, P＜0.05.See Table 17.
Table 17 present composition (Hu Xinkang) to myocardial ischemia organize the influence that NFkBP65 expresses (n=5,
Individual/mm
2)
Annotate: compare * P＜0.05 * * P＜0.01 with model group; Compare Δ P＜0.05 with diltiazem.
Treating myocardial ischemia damage can suppress IKB expresses, and the present composition can raise its expression, significance is arranged, P＜0.05 with model group and matched group difference.See Table 18.
The influence that table 18 present composition (Hu Xinkang) is expressed IKB (n=5,
Individual/mm
2)
Annotate: with the model group ratio, * P＜0.05 * * P＜0.01; Compare Δ P＜0.05 with diltiazem.
NFkBP65, IKB have the expression of reduced levels under the normal condition, NFkBP65 increase IKB expresses and is suppressed behind the treating myocardial ischemia damage, diltiazem and protect the expression that heart health extract all can be reduced NFkBP65, raise IKB, with model group, difference has significance, P＜0.05, and diltiazem is not as protecting heart health extract, P＜0.05.
Result of the test shows that the present composition can obviously improve the inflammatory factor of rats with myocardial ischemia, and downward modulation blood vessel adhesion factor-1 and NO kinases are regulated the expression of nuclear factor kB and IkB, and influencing the inflammation signal path is one of its possibility mechanism of action.
To sum up, the present composition acts on the inflammation path by many target spots and realizes function of resisting myocardial ischemia.
List of references:
[1] Gu Juan, Luo Haiyan, An Lianying etc. the research of salvianolic acid water extraction process [J]. research and development of natural products, 2005,17 (6): 781-783.
[2] Fang Xinsheng, Tan Xiaomei, Wang Jianhua. the technical study of purification with macroreticular resin Radix Salviae Miltiorrhizae total phenolic acids [J]. Chinese herbal medicine, 2006,37 (10): 1502-1504.
[3] Luo Xiaojian, Zhou Shuyu, wangdan flower bud etc.Uniform Design is optimized Radix Notoginseng total arasaponins extraction process [J]. Shenyang Pharmaceutical University's journal, 2002,19 (2): 122-124.
[4] Li Jialin, the cloud unicorn. piperine Study on extraction [J] in the mongolian medicine Fructus Piperis Longi. Chinese national medicine magazine, 2007,13 (4): 63-64.
Claims (11)
1. Chinese medicine composition that is used for the treatment of coronary heart disease, the said composition active component is made up of Radix Salviae Miltiorrhizae total phenolic acids, Radix Notoginseng total arasaponins, Fructus Piperis Longi total alkaloids, succinum total sesquiterpene, the weight proportion of used each raw material is: Radix Salviae Miltiorrhizae total phenolic acids 1.25-1.5 part, Radix Notoginseng total arasaponins 1-1.5 part, Fructus Piperis Longi total alkaloids 0.02-0.13 part, succinum total sesquiterpene 0.02-0.09 part.
2. according to the pharmaceutical composition of the described treatment coronary heart disease of claim 1, the purity of wherein said Radix Salviae Miltiorrhizae total phenolic acids is for being not less than 50%.
3. according to the pharmaceutical composition of the described treatment coronary heart disease of claim 1, the purity of wherein said Radix Notoginseng total arasaponins is for being not less than 50%.
4. according to the pharmaceutical composition of the described treatment coronary heart disease of claim 1, the purity of wherein said Fructus Piperis Longi total alkaloids is for being not less than 50%.
5. according to the pharmaceutical composition of the described treatment coronary heart disease of claim 1, the purity of wherein said succinum total sesquiterpene is for being not less than 50%.
6. the pharmaceutical composition of treatment coronary heart disease according to claim 1, wherein said Radix Salviae Miltiorrhizae total phenolic acids is extracted by Radix Salviae Miltiorrhizae, described Radix Notoginseng total arasaponins is extracted by Radix Notoginseng, and described Fructus Piperis Longi total alkaloids is extracted by Fructus Piperis Longi, and the succinum total sesquiterpene is extracted by succinum.
7. according to the pharmaceutical composition of the described treatment coronary heart disease of claim 6, wherein said Radix Salviae Miltiorrhizae total phenolic acids prepares according to following method: red rooted salvia water or different concentration ethanol are extracted, and extracting solution reclaims ethanol, is concentrated into proper volume; The concentrated solution absorption with macroporous adsorbent resin washes with water to effluent colourlessly earlier, and reuse low-concentration ethanol desorption is collected ethanol elution, reclaims ethanol, and drying promptly gets Radix Salviae Miltiorrhizae total phenolic acids, and wherein the content of salvianolic acid B must not be less than 30%.
8. according to the pharmaceutical composition of the described treatment coronary heart disease of claim 6, wherein said Fructus Piperis Longi total alkaloids prepares according to following method: the Fructus Piperis Longi medical material is adopted SFE-CO
2The extraction or alcohol extraction, purified, the recrystallization of the total alkaloids that obtains promptly get the Fructus Piperis Longi total alkaloids, wherein content of piperine must not be less than 30%, the employing cyclodextrin inclusion compound, the result with 2～6 times to supercritical CO
2The β-CDBao He of extract adds 4 times of water gagings, and enclose time 2h promptly gets Fructus Piperis Longi total alkaloids beta-CD inclusion.
9. according to the pharmaceutical composition of the described treatment coronary heart disease of claim 6, wherein said Radix Notoginseng total arasaponins prepares according to following method: pseudo-ginseng is adopted 70% ethanol extraction, filter, filtrate decompression concentrates, and crosses macroporous adsorptive resins, use 80% ethanol elution, eluent decolouring back concentrating under reduced pressure, refining, drying, promptly get Radix Notoginseng total arasaponins, contain wherein that arasaponin R1 must not be less than 5.0%, ginsenoside Rg 1 must not be less than 20.0%, ginsenoside Rb 1 must not be less than 25.0%.
10. according to the pharmaceutical composition of the described treatment coronary heart disease of claim 6, wherein said succinum total sesquiterpene prepares according to following method: the succinum medical material is adopted SFE-CO
2Extraction promptly get triterpenes components content greater than 50% succinum total sesquiterpene, the employing cyclodextrin inclusion compound, the result with 2～6 times to supercritical CO
2The β-CDBao He of extract adds 4 times of water gagings, and enclose time 2h promptly gets succinum total sesquiterpene beta-CD inclusion.
11. according to the application of any described pharmaceutical composition of claim 1-10 in preparing treatment coronary heart disease and heart failure, cardiac arrhythmia medicine.
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| CN1709458A (en) * | 2005-07-08 | 2005-12-21 | 石保贵 | Medicine for treating coronary clisease |
| CN1943769A (en) * | 2006-10-17 | 2007-04-11 | 吴鹏 | An external pharmaceutical for treatment of arrhythmia, coronary heart disease and angina pectoris |
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| CN1541677A (en) * | 2003-11-06 | 2004-11-03 | 李德峰 | Medicinal composition for treating coronary disease and its preparation and application |
| CN1709458A (en) * | 2005-07-08 | 2005-12-21 | 石保贵 | Medicine for treating coronary clisease |
| CN1943769A (en) * | 2006-10-17 | 2007-04-11 | 吴鹏 | An external pharmaceutical for treatment of arrhythmia, coronary heart disease and angina pectoris |
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| CN105343232A (en) * | 2015-11-11 | 2016-02-24 | 安徽生物肽产业研究院有限公司 | Composition of effective parts of ground beetle small peptides for treating cardiovascular diseases |
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